SUMMARY Androgen ablation therapy has been the gold standard for treating advanced stage prostate cancer (PCa) since the 1960s. Initially, the PCa patients respond to hormone ablation very positively. However, over time these tumors almost always become resistant to androgen ablation therapy, and tumors begin to grow again. Recent studies found after failure of the new drugs that block androgen action, PCa has increased neuroendocrine phenotype. Understanding the mechanisms through which PCa cells gain neuroendocrine phenotype is critical for the development of novel therapeutics. Studies have shown that the expression of EZH2 is increased in advanced stage PCa and elevated EZH2 is associated with a poor outcome of PCa. A recent gene expression profiling study has identified EZH2 and polycomb proteins the top genes overexpressed in neuroendocrine PCa. Additionally, studies using human prostate specimens have shown that inactivation of p53/pRb frequently occurs in neuroendocrine PCa. Inactivation of p53/pRb induces the expression of EZH2. Based on these data, we hypothesize EZH2 induction by inactivation of p53/pRb promotes neuroendocrine differentiation of PCa. This hypothesis will be tested by the following specific aims: Aim 1, to determine the role of EZH2 in neuroendocrine differentiation of PCa in vitro. The working hypothesis is overexpression of EZH2 is sufficient to induce neuroendocrine differentiation of PCa cells and elevated expression of EZH2 is essential for inactivation of p53/pRb induced neuroendocrine differentiation of PCa. Aim 2, to determine the role of EZH2 in neuroendocrine PCa in vivo using human neuroendocrine PCa xenograft models. The working hypothesis is pharmacological inhibition of EZH2 inhibits the growth of neuroendocrine prostate tumors.